My goals in seeking a K23 award are to investigate HIV infection and to develop a career in translational research. My particular research interest is in the determination of important immune responses needed in an effective preventative or therapeutic HIV vaccine. I have assembled a mentoring committee composed of internationally recognized scientists with strong track records in translational research; I will obtain training in clinical research methodologies and additional laboratory training in immunologic methodologies; and I propose to conduct a series of mentored research projects that will provide opportunities for me to acquire the "hands-on" training needed to become a productive, independent clinical researcher. Many HIV-infected patients have low levels of HIV viral replication despite antiretroviral therapy. This viremia represents drug-resistant virus with reduced replicative capacity. These patients maintain increased CD4+ T cell counts. A significant proportion of these patients, however, will ultimately develop high-level viremia. I am interested in investigating the immunologic parameters that may predict which patients may develop high-level viremia, as well as study the effect of drug-resistant viremia on the entire immune system. I propose the following specific aims: (1) To assess whether higher HIV-specific CD4+ and CD8+ T cell responses are associated with the control of drug-resistant HIV replication in patients on antiretroviral therapy; (2) To assess whether evidence of an aging immune system is associated with CD4+ T cell loss in patients with partially controlled viremia on antiretroviral therapy; (3) To assess whether the ability of T cells to respond to immunization is altered in patients with partially controlled viremia on antiretroviral therapy. We hypothesize that the maintenance of high-level HIV-specific T cell responses will predict maintenance of partial control of viremia; we will follow these patients longitudinally with serial measurements of HIV-specific T cell function. Furthermore, the presence of partial HIV viremia is associated with an increased proportion of effector CD4+ T cells, a sign of an aging immune system. We hypothesize that these patients will sustain CD4+ T cell loss; we will follow them with serial measurements of T cell immunophenotyping. In addition, we hypothesize that patients with partial viremic control will have reduced responses to immunization, an estimate of in vivo immune competence. For Aims 1 and 2, I will use samples collected in an established cohort study. For Aim 3, I will conduct a prospective interventional study, where I will design and implement an independent clinical research project.